TRAIL-R as a Negative Regulator of Innate Immune Cell Responses

Abstract

TRAIL receptor (TRAIL-R) signaling has been implicated in inducing apoptosis in tumor cells, but little is understood about its physiological function. Here, we report the generation and characterization of TRAIL-R(-/-) mice, which develop normal lymphocyte populations but possess enhanced innate immune responses. TRAIL-R(-/-) mice exhibited increased clearance of murine cytomegalovirus that correlated with increased levels of IL-12, IFN-alpha, and IFN-gamma. Stimulation of macrophages with Mycobacterium and Toll-like receptor (TLR)-2, -3, and -4, but not TLR9, ligands resulted in high levels of TRAIL upregulation and enhanced cytokine production in TRAIL-R(-/-) cells. The immediate-early TLR signaling events in TRAIL-R(-/-) macrophages and dendritic cells are normal, but I kappa B-alpha homeostatic regulation and NF-kappa B activity at later time points is perturbed. These data suggest that TRAIL-R negatively regulates innate immune responses.

New insights into apoptosis signaling by Apo2L/TRAIL

“…However, the observed effects were modest; moreover, given that differences in biological activity may exist between recombinant soluble versions of Apo2L/TRAIL , the practical implications of these studies are difficult to assess, because biochemical characterization of the ligand variant used was not provided. Importantly, studies with mDR5-knockout mice suggest that this receptor is involved in suppressing innate immunity to pathogens by inhibiting, rather than stimulating, the NF-kB pathway (Diehl et al, 2004). In agreement with these latter findings, lung tumors induced experimentally in mDR5-null mice display elevated levels of NFkB (Finnberg et al, 2008).…”

“…Furthermore, treatment of wild-type mice with Apo2L/TRAILblocking antibodies exacerbated development of experimental autoimmune disease (Hilliard et al, 2001;Cretney et al, 2005). Infection of mDR5-knockout mice with murine cytomegalovirus was associated with an augmented antiviral response (Diehl et al, 2004). Consistent with this latter possibility, Apo2L/TRAILdeficient mice displayed enhanced resistance to Listerial infection (Zheng et al, 2004).…”

“…In contrast to humans, mice possess only one cognate DR for Apo2L/ TRAIL, dubbed mDR5 (or mTRAILR2 and mKIL-LER), which shares a similar degree of homology with human DR4 and DR5 (Wu et al, 1999). mDR5-knockout mice are viable and develop normally (Diehl et al, 2004). Similarly, Apo2L/TRAIL-knockout mice do not display any overt developmental defects, indicating that, as in zebrafish, Apo2L/TRAIL signaling is not essential for normal mouse embryonic development (Cretney et al, 2002).…”

“…Its selective expression in immune effector cells suggests that Apo2L/TRAIL may contribute to shaping the immune repertoire and/or regulating the immune response. Genetic ablation of either Apo2L/TRAIL or mDR5 in mice does not affect the resting immune cell populations (T, B, macrophage, dendritic and natural killer cells) (Cretney et al, 2002;Diehl et al, 2004). Patients with multiple sclerosis or systemic lupus erythematosus have elevated serum levels of Apo2L/TRAIL, suggesting upregulation of this ligand in certain autoimmune disorders (Wandinger et al, 2003;Lub-de Hooge et al, 2005).…”

TWEAK shall inherit the earth

“…In particular, TRAIL-R knockout mice are able to clear murine cytomegalovirus infections better than wild-type mice, and this correlates with increased levels of IL-12 and IFNg. 19 The cytokines IL-12 and IFNg also play key roles in influencing the transition from the innate to adaptive immune responses. Both IL-12 and IFNg direct the development of the T helper 1 subtype (T H 1), which is generally more effective at combating tumours than the T H 2 subtype, because it induces CD8 þ effector T cell responses rather than IgG responses.…”